Trials Produce Practice-Changing Results for Brain Cancer

The standard treatment that some patients with brain cancer receive is likely to change, based on findings from two large clinical trials presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago this week.

Both trials showed that administering the chemotherapy drug temozolomide (Temodar®) in addition to radiation therapy increased how long patients lived overall and without their disease progressing. The trial investigators and other leading brain cancer researchers agreed that the results of the two trials will change the standard of care.

In addition to improving survival, both trials resolved important questions about whether specific groups of patients benefit from receiving temozolomide, said Mark Gilbert, M.D., chief of NCI’s Neuro-Oncology Branch. “These are important studies in the brain cancer field,” he said.

Improved Survival in Older Patients with Glioblastoma

One of the trials tested the regimen in patients with glioblastoma, one of the most aggressive types of brain cancer. The trial, led by the Canadian Cancer Trials Group (CCTG), focused on patients over the age of 65.

This is an important group of patients, said the trial’s leader, James Perry, M.D., of Sunnybrook Research Institute in Toronto. The peak age for glioblastoma diagnoses is 64, Dr. Perry explained, and overall incidence of the disease has been creeping up in recent years. A pivotal 2005 trial showed that temozolomide can improve how long patients with glioblastoma live. The trial, however, was restricted to patients younger than 70, and very few patients over age 65 were included in the trial, he said.

Because of concerns about serious side effects of chemotherapy, radiation alone has been the standard of care for patients aged 70 and older, Dr. Gilbert explained.

“In fact, the radiation course is often truncated to 2, 3, or 4 weeks rather than the 6 weeks that is standardly used, along with chemotherapy, in the younger patient population,” he said.

In the CCTG trial, more than 560 patients aged 65 and older with advanced glioblastoma were randomly assigned to receive either short-course radiation alone or radiation plus temozolomide, given both at the same time (concurrent) and for an additional 12 rounds after radiation (adjuvant).

Median overall survival in patients treated with both radiation and temozolomide was 9.3 months, compared with 7.6 months in patients who received radiation therapy alone. The radiation and temozolomide combination also modestly improved progression-free survival.

The 1-year and 2-year survival rates were 37.8% and 10.4% with radiation plus temozolomide, versus 22.2% and 2.8% with radiation therapy alone.

The researchers also identified a group of patients for whom the addition of temozolomide was especially beneficial: Patients whose tumors have an alteration of the MGMT gene, known as promoter methylation, had an overall survival of 13.5 months compared with 7.7 months in patients with the alteration who received only radiation therapy.

This was not necessarily a surprise, Dr. Perry noted. Earlier studies have shown that methylation of the MGMT promoter in glioblastoma is associated with better prognosis and improved response to chemotherapy. Approximately 46% of patients with glioblastoma have MGMT promoter methylation, Dr. Perry explained, a proportion that is consistent regardless of age at diagnosis.

Although there was “substantially more benefit” in patients whose tumors had MGMT promoter methylation, he said, “to our surprise, unmethylated patients also derived clinical benefit.”

Adding temozolomide to radiation did not increase the toxicity of treatment, Dr. Perry said. In fact, he said, “most patients were able to easily complete the treatment plan.”

Survival Improved for Rare Brain Cancer

The other trial, dubbed CATNON, included patients with a rare type of low-grade glioma called anaplastic glioma, of which only 1,200 to 1,500 cases are diagnosed each year in the United States. The trial enrolled only patients whose tumors lack the 1p/19q co-deletion, a molecular alteration in chromosomes 1 and 19 that is commonly seen in patients with some low-grade gliomas, named anaplastic oligodendroglioma.

Patients whose tumors have the 1p/19q co-deletion have a better prognosis and respond better to chemotherapy than patients whose tumors lack the alteration, explained the trial’s lead investigator, Martin van den Bent, M.D., from the Erasmus MC Cancer Institute in the Netherlands.

So, given the need for new treatment options for patients whose tumors lack the 1p/19q co-deletion, Dr. van den Bent said, the CATNON trial was designed to determine whether these patients might benefit from adding temozolomide to standard radiation therapy.

The trial, which was led by the European Organization for Research and Treatment of Cancer (EORTC), involved nearly 120 institutions from around the world. Approximately 750 patients enrolled and were randomly assigned to one of four treatment arms: radiation therapy alone, concurrent radiation and temozolomide, radiation followed by adjuvant temozolomide, or radiation and concurrent temozolomide followed by adjuvant temozolomide.

At 5 years, 56% of patients who received adjuvant temozolomide (arms 3 and 4) were still alive compared with 44% of patients who did not (arms 1 and 2). Adjuvant temozolomide also more than doubled how long patients lived without their disease progressing: 42.8 months compared with 19 months.

Given the survival advantages seen when temozolomide is given to patients with glioblastoma, some oncologists already offer it to their patients with anaplastic glioma, explained Brian Alexander, M.D., of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute.

From the perspective of potential side effects, it’s not unexpected that temozolomide is given to such patients, Dr. Alexander continued. “Temozolomide has a degree of toxicity, but it is generally well tolerated,” he said.

Of the two trials presented at ASCO, CATNON “will have the largest impact, because it has answered some fundamental questions about the role of adjuvant chemotherapy in patients with anaplastic glioma that does not have the 1p/19q chromosome loss,” Dr. Gilbert said.

Dr. van den Bent and his colleagues are performing molecular analyses of tumor samples to determine whether patient treatment response correlates with the presence of other commonly seen genetic alterations in lower-grade gliomas, including mutations in the IDH1 gene.

They are also continuing to follow the survival outcomes in patients treated with radiation alone and concurrent temozolomide, he said.

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